Molecules that interact with the antigen-specific receptor on T-cells, including peptides bound to major histocompatibility complex (MHC) molecules, antibodies against the antigen specific receptor, and mitogenic lectin, fail on their own to stimulate T cells to proliferate. At least one additional signal is required. This second signal is referred to as co-stimulation, and it is delivered by antigen-presenting cells. The molecular nature of co-stimulation has been sought for many years in order to facilitate therapeutic strategies for suppressing immune responses. The goal of these studies is to dissect further the molecular mechanisms of co-stimulation by the use of naturally occurring immunosuppressive agents. Findings to date indicate that glucocorticoids inhibit activation of NF-AT and IL-2Ralpha expression but not the tyrosine phosphorylation and calcium influx when cells are stimulated via CD2. IL-2 production is inhibited by glucocorticoids in cells treated with phorbol ester and anti-CD28.